The major objectives for the proposed research are to develop sensitive and nontraumatic methods with which to study central nervous system (CNS) cholinergic function in man and to explore the extent of cholinergic involvement in a variety of mental and neurologic disease states. 1. Levels of choline (Ch) and acetylcholine (ACh), the interrelationship of these two agents, and their significance in human blood will be determined in normal controls and in clinically depressed patients before and during treatment with either amitriptyline or lithium. Transport of Ch and its conversion to ACh in red blood cells (RBC) will also be determined in blood obtained from the above subjects. 2. We have demonstrated that one can achieve efficient labeling of mouse brain ACh by supplying deuterium-labeled Ch in the diet. The extent to which blood cholinergic parameters reflect brain Ch and ACh function will be determined in such animals after administration of pharmacologic agents which are known to perturb central cholinergic function, and following treatment with amitriptyline, nortriptyline and lithium. These data, when correlated with those obtained in I should determine the validity of utilizing blood components as an index of central cholinergic function in man. 3. The effect of amitriptyline, nortriptyline and lithium on CNS cholinergic parameters will be determined directly in laboratory animals. Brain levels of Ch and ACh, activity of the enzymes cholineacetyltransferase and acetylcholinesterase, turnover rate of ACh in the CNS, and metabolism of other monoaminergic neurotransmitters in the brain will be examined. Gas chromatographic/mass spectrometric determinations of neurotransmitters, neurotransmitter metabolites and drug and metabolite levels will feature prominently in all these studies.